Although smoking is the major cause of lung cancer, there remains many gaps in our knowledge of its etiology, which is thought to be heterogeneous by smoking status, gender, and histological subtype. The purpose of this nested case-control study with 1,384 lung cancer cases and 1,601 controls from the Women's Health Initiative (WHI) cohort is to elucidate the risk factors of lung cancer in these individual subgroups. We will focus on the serum levels of 5 physiological factors (IGF-I, HGF, NGF, insulin, and IL-6) that activate and one factor (IGFBP-3) that inhibits the epidermal growth factor receptor (EGFR) signaling network, which encompasses multiple pathways regulating cell proliferation, survival, and migration. We will examine if serological levels of the 6 activators/inhibitor are associated with risk of lung cancer, and whether the associations vary depending on smoking status and histological subtype. In addition, previously identified genetic variations in the EGFR signaling network that are associated with lung cancer will also be incorporated to assess how serological and genetic factors in the EGFR signaling network may interact to affect lung cancer risk. The large WHI cohort provides a valuable opportunity to study the heterogeneous etiology of lung cancers in subgroups of women. Identifying susceptibility factors in smokers and risk factors in never- smokers will contribute towards our understanding of women's health and may also provide insights into the development of lung cancer prevention programs for women. PUBLIC HEALTH RELEVANCE: This study will examine, in postmenopausal women, if serum levels of 6 physiological factors that activate/inhibit the epidermal growth factor receptor (EGFR) signaling network are associated with risk of lung cancer in smokers and non-smokers. As the incidence of lung cancer in never-smokers is significantly higher in women than men, elucidating the risk factors in female never-smokers would contribute towards our understanding of women's health. Identifying the host susceptibility factors in smokers would help to focus chemoprevention studies. This study may also provide insights into the therapeutic management of lung cancer. If the levels of these serological factors are involved in the pathogenesis of lung cancer, then testing for and modifying their aberrant levels could be an alternative treatment as well as a chemoprevention strategy for lung cancer.